myeloablative conditioning, prophylactic defibrotide and haplo allosct for patients with sickle cell disease

Conditions: Sickle Cell Disease

Summary: this is a follow-up trial to nymc 526 (nct01461837) to assess the safety, efficacy and toxicity of administering defibrotide prophylaxis for high-risk sickle cell or beta thalassemia patients undergoing a familial haploidentical allogeneic stem cell transplantation with cd34 enrichment and t-cell addback. this patient population historically has a risk of developing sinusoidal obstructive syndrome (sos) and defibrotide has demonstrated efficacy in treatment of sos. the funding source is fda oopd.


Eligibility criteria:
inclusion criteria: * disease: homozygous hemoglobin s disease, or hemoglobin s b0/+ thalassemia, or hemoglobin sc disease, or beta thalassemia intermedia/majora * patients must demonstrate one or more of the following sickle cell disease complications (or patients in cohort 2 can meet other high risk criteria instead) * clinically significant neurologic event (stroke) or any neurologic deficit lasting \>24 hours that is accompanied by an infarct on cerebral mri * acute chest syndrome in the preceding two year period prior to enrollment that have failed, been non-compliant or declined hydroxyurea treatment, or prior to chronic rbc transfusion therapy, exchange transfusion or erythrocyte pheresis. * recurrent painful events (at least 3 in the 2 years prior to enrollment or prior to chronic chronic rbc transfusion therapy, exchange transfusion or erythrocyte pheresis). * abnormal tcd study requiring starting on chronic transfusion therapy and/or exchange transfusions. * at least one silent infarct lesion on a mri scan of the head. or (directly or probably related to scd) * sickle cell nephropathy; * splenic sequestration requiring rbc transfusion; * aplastic crisis requiring rbc transfusion; * avascular necrosis of the hip diagnosed by mri; * two episodes or more of leg ulcerations; * recurrent priapism . * infant dactylitis. * or for cohort #2 only: patient must be between 18 and 34.99 years of age, patients must demonstrate at least two of the following: * wbc \> 13,500 cells/microliter at baseline when not acutely ill (on two separate occasions) \> 2 weeks from a voc event or hospitalization. * tricuspid regurgitant jet velocity (trv) \> 3.0 m/s * requiring chronic monthly transfusions ( \> 12 transfusions in the 12 months) * history of sepsis * n-terminal pro-brain natriuretic peptide (nt-probnp) \> 160 ng/l at clinical baseline when not acutely ill or hospitalized. * all patients must meet disease, age, organ function and donor criteria; exclusion criteria: * patients who are receiving concomitant systemic anticoagulants and/or fibrinolytic therapies. * patients with a previously known hypersensitivity reaction to defibrotide. * females who are pregnant or breast-feeding are not eligible * scd patients with documented uncontrolled infection at the time of study entry are not eligible. * scd patients who have an unaffected hla matched family donor willing to proceed to donation will not be eligible for this study. * karnofsky or lansky (age appropriate) performance score \<50% (hemiplegia alone secondary to a previous stroke is not an exclusion) * demonstrated lack of compliance with medical care. * patients with clinically significant fibrosis or cirrhosis of the liver will not be eligible. * patients who have previously received a hsct will not be eligible. * patients with contraindications to the use of defibrotide

Keywords: stem cell transplantation sickle cell disease haploidentical defibrotide